Abstract
Prostate cancer is featured by its heterogeneous nature, which indicates a different prognosis. Castration-resistant prostate cancer (CRPC) is a hallmark of the treatment-refractory stage, and the median survival of patients is only within two years. Neuroendocrine prostate cancer (NEPC) is an aggressive variant that arises from de novo presentation of small cell carcinoma or treatment-related transformation with a median survival of 1–2 years from the time of diagnosis. The epigenetic regulators, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been proven involved in multiple pathologic mechanisms of CRPC and NEPC. LncRNAs can act as competing endogenous RNAs to sponge miRNAs that would inhibit the expression of their targets. After that, miRNAs interact with the 3’ untranslated region (UTR) of target mRNAs to repress the step of translation. These interactions may modulate gene expression and influence cancer development and progression. Otherwise, epigenetic regulators and genetic mutation also promote neuroendocrine differentiation and cancer stem-like cell formation. This step may induce neuroendocrine prostate cancer development. This review aims to provide an integrated, synthesized overview under current evidence to elucidate the crosstalk of lncRNAs with miRNAs and their influence on castration resistance or neuroendocrine differentiation of prostate cancer. Notably, we also discuss the mechanisms of lncRNA–miRNA interaction in androgen receptor-independent prostate cancer, such as growth factors, oncogenic signaling pathways, cell cycle dysregulation, and cytokines or other transmembrane proteins. Conclusively, we underscore the potential of these communications as potential therapeutic targets in the future.
Highlights
Prostate cancer (PCa) is the second most commonly diagnosed malignancy, leading to 6.8% of cancer-related deaths in the male population worldwide in 2020 [1]
As a member of the steroid hormone nuclear receptor family, androgen receptor (AR) can act as a nuclear transcription factor with its coactivators and directly binds to androgen response elements (AREs) to mediate its target gene function
LncRNA–miRNA–mRNA networks appear to be widespread in PCa cells and tissues
Summary
Prostate cancer (PCa) is the second most commonly diagnosed malignancy, leading to 6.8% of cancer-related deaths in the male population worldwide in 2020 [1]. The treatment and the prognosis of PCa are determined by the stratified risk group on the basis of prostate-specific antigen (PSA) level, the sum of Gleason patterns, and the clinical stage. Compared with localized PCa that can be actively surveyed without management, the treatment of advanced PCa, requiring systemic therapy, is much more complicated and lethal [3,4,5]. Androgen deprivation therapy (ADT) is usually the first-line systemic treatment in advanced PCa, according to the canonical mechanism of the androgen receptor (AR) signaling pathway [6]. The innate diversity of PCa cells can adapt to androgen deprivation, resulting in activation of AR signal even under a low level of serum androgen and advancing to a worse condition named castration-resistant prostate cancer (CRPC) [7,8]
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